It is well-known that aged individuals, an expanding demographic in the United States, have a dramatically increased risk of numerous debilitating diseases including bone fractures, cardiovascular disease, cognitive impairment, diabetes and cancer. Although the molecular basis of the progressive loss of homeostatic reserve with aging is controversial, there are several lines of evidence that implicate accumulated DNA damage as a major determinant in the progression of age-related pathology. In particular, the majority of human progerias (or syndromes of accelerated aging) are caused by inherited mutations in genes required for genome repair and maintenance, including XPF. ERCC1-XPF protein complex is a highly conserved endonuclease that is required for at least two DNA repair mechanisms: nucleotide excision repair (NER) and DNA interstrand crosslink repair. We have several progeroid mouse models of ERCC1-XPF deficiency including Ercc1-/- and Ercc1-/ , which express levels of ERCC1-XPF at 0% and 10% of normal, respectively. The average life span of the Ercc1-/- mice is 21 days and that of the Ercc1-/ mice is 7 months. Both mice develop age-related pathologies including ataxia, kyphosis, cachexia, disc degeneration, osteoporosis, incontinence, epidermal atrophy, sarcopenia, bone marrow degeneration and liver as well as kidney dysfunction. We previously isolated and characterized a population of muscle-derived stem cells (MDSCs) that displays a high regenerative capacity in various tissues of the musculoskeletal system. Our preliminary results suggest that MDSCs isolated from progeroid ERCC1-XPF deficient mice have proliferation and differentiation defects. Furthermore, injection of wild type (wt) MDSCs into Ercc1-/- mice results in their engraftment into multiple tissues and significantly extends lifespan. Thus we hypothesize that a defect in the adult stem cell compartment in ERCC1-XPF deficient mice is involved in their dramatically accelerated aging and that stem cell therapy may represent a potential strategy to prevent or delay age-associated debilitating changes. The focus of this proposal will be on documenting and characterizing the defect in MDSCs in our unique progeroid mouse models and on demonstrating the ability of transplantation of functional MDSCs to delay the onset of age-related pathologies. PUBLIC HEALTH RELEVANCE: Aging is characterized by the progressive erosion of all organ systems which places the elderly at an increased risk of numerous debilitating diseases and organ system failures including cardiovascular disease, dementia, bone fractures, sarcopenia, and cancer. Demographic studies indicate that the number of individuals aged greater than 65 will double in the next 25 years and impose an unprecedented burden on the U.S. health care system. This research proposal is highly significant in that it has the potential to not only reveal a biological mechanism(s) of aging (defect in stem cell compartment), but could also lead to the development of stem cell therapies which could delay or ameliorate the pathologies associated with aging;therefore, identifying strategies, such as stem cell transplantation, is essential for maintaining the health of our aging population.